The acute respiratory distress syndrome (ARDS) is a major source of morbidity and mortality, with nearly 200,000 cases annually in the US and a mortality of 30-40%. Despite significant research, no effective treatments have been identified; consequently, there has been increased interest in preventative strategies. Cigarette smoke exposure has recently been identified as a risk factor for the development of ARDS. However, few studies have directly examined the potential mechanisms that underlie this relationship. My preliminary data suggests that cigarette smoke is associated with increased baseline alveolar epithelial injury and an exaggerated inflammatory response. Given the significant role that alveolar epithelial injury and inflammation play in the pathogenesis of ARDS, these findings have encouraged me to further study these pathways in cigarette smokers. The proposed project aims to investigate the mechanisms through which cigarette smoke predisposes patients to develop ARDS by studying plasma and bronchoalveolar lavage (BAL) biomarkers of alveolar epithelial injury and inflammation in four distinct cohorts, three of which have completed enrollment. I hypothesize the cigarette smoke is associated with baseline alveolar epithelial injury that primes the lung to develop excessive injury and inflammation in the presence of a second-hit. In Aim 1, I will measure baseline levels of alveolar epithelial injury and inflammation in two cohorts of healthy subjects. I hypothesize that in my first cohort, which is comprised of otherwise healthy chronic alcoholics and matched controls, that cigarette smoke will be associated with baseline alveolar epithelial injury (Hypothesis 1a). I hypothesize that in my second cohort, which consists of healthy volunteers undergoing inhalation of lipopolysaccharide (LPS), cigarette smoke will be associated with increased alveolar epithelial injury and inflammation (Hypothesis 1b). In Aim 2, I will measure biomarkers of alveolar epithelial injury and inflammation in two distinct cohorts of critically ill patients at risk for ADS to determine if cigarette smoke is associated with increased injury and inflammation in the presence of a second-hit, such as trauma, aspiration, pneumonia or sepsis. I hypothesize that in the presence of a risk factor for ARDS, cigarette smoke exposure will be associated with increased alveolar epithelial injury and inflammation (Hypotheses 2a & 2b). In addition, I hypothesize that in patients who go on to develop ARDS, the severity of epithelial injury and inflammation will be greater amongst cigarette smokers (Hypotheses 2a & 2b). These studies have the potential to provide insight into the mechanisms by which cigarette smoke predisposes patients to ARDS, laying the groundwork for future prevention and targeted treatment strategies for ARDS.